Treatment of Subarachnoid Hemorrhage With Human Albumin

An estimated 37,500 people in the United States have subarachnoid hemorrhage (SAH) every
year. SAH is usually secondary to a brain aneurysm that has burst. In SAH the bleeding
accumulates around the lining of the brain. SAH is associated with a 51percent mortality
rate, and one third of survivors are left functionally dependent. Cerebral vasospasm, which
is a delayed narrowing of the cerebral arteries following SAH, has been identified as the
most important reason for neurological deterioration and bad outcome in cases of SAH.
Cerebral vasospasm may be caused by multiple mechanisms.

Treatment with a neuroprotective agent, such as human albumin (HA), may be beneficial for
prevention of cerebral vasospasm and improved clinical outcome in patients with SAH. HA is
a major protein found in blood and is responsible for maintaining fluid balance in the
vascular system (blood vessels). The purpose of this study is to determine the safety and
tolerability of 25 percent HA therapy in patients with SAH. This open-label,
dose-escalation study will provide necessary information for a future definitive phase III
clinical trial on the efficacy of treatment with HA in patients with SAH.

The study will enroll 80 patients at 5 centers in the US. Patients with eligible SAH will
first undergo surgical or endovascular repair, which is considered standard care.
Endovascular repair is a repair of the aneurysm from the inside of the blood vessel.

Following neurosurgical or endovascular treatment, participants will be given a daily
infusion of HA for 7 days. The HA dose will be allocated as follows: the first tier (20
patients) will receive 0.625 grams (g) of HA per kilogram (kg) of body weight; patients in
the second tier will receive 1.25g of HA per kg; patients in the third tier will receive
1.875g of HA per kg; and patients in the fourth tier will receive 2.5g of HA per kg. Safety
and tolerability will be evaluated by the Data and Safety Monitoring Board (DSMB) after each
tier is completed and before the study advances to the next dose tier. A specific safety
threshold for congestive heart failure and other adverse events has been defined based on
data from previous studies.

In the follow-up phase, patients will participate in study-related evaluations of their
health at 15 days and three months. Duration of the study for participants is 90 days.

Inclusion Criteria:

- Patients (male or female) must be at least 18 but younger than 80 years of age.

- Onset of new neurological signs of subarachnoid hemorrhage within 72 hours at the
time of evaluation and initiation of treatment with 25% human albumin.

- Clinical signs consistent with the diagnosis of subarachnoid hemorrhage including
severe thunderclap headache, cranial nerve abnormalities, decreased level of
consciousness, meningismus and focal neurological deficits.

- Computed tomography demonstrates subarachnoid hemorrhage.

- Cerebral angiography reveals the presence of saccular aneurysm(s) in a location that
explains the subarachnoid hemorrhage.

- Treatment of cerebral aneurysm must be carried out prior to initiation of HA infusion
but within 72 hours of symptom onset. Accepted treatments of aneurysms include
surgical clipping or endovascular embolization.

Exclusion Criteria:

- Time of symptom onset cannot be reliably assessed.

- No demonstrable aneurysm by cerebral angiography.

- Evidence of traumatic, mycotic, or fusiform aneurysm by cerebral angiography.

- World Federation of Neurological Surgeons scale of IV and V

- Computed tomography scale of 0-1

- History within the past 6 months, and/or physical findings on admission of
decompensated congestive heart failure (NYHA Class IV or congestive heart failure
requiring hospitalization).

- Patient has received albumin prior to treatment assignment during the present
admission.

- Hospitalization for or diagnosis of acute myocardial infarction within the preceding
3 months.

- Symptoms or electrocardiographic signs indicative of acute myocardial infarction on
admission.

- Electrocardiographic evidence and/or physical findings compatible with second- or
third-degree heart block, or of cardiac arrhythmia associated with hemodynamic
instability.

- Echocardiogram performed before treatment revealing a left ventricular ejection
fraction ≤ 40% (if available).

- Serum creatinine > 2.0 mg/dl or creatinine clearance < 50 ml/min.

- Pregnancy, lactation or parturition within previous 30 days.

- Allergy to albumin.

- Severe prior physical disability that precludes evaluation of clinical outcome
measures.

- History of chronic lung disease

- Current participation in another drug treatment protocol.

- Severe terminal disease with life expectancy less than 6 months.